Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals’ overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one’s own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.
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Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011; 365: 1597–1604.
Horton TJ, Drougas H, Brachey A, Reed GW, Peters JC, Hill JO . Fat and carbohydrate overfeeding in humans: different effects on energy storage. Am J Clin Nutr 1995; 62: 19–29.
Apolzan JW, Bray GA, Smith SR, de Jonge L, Rood J, Han H et al. Effects of weight gain induced by controlled overfeeding on physical activity. Am J Physiol Endocrinol Metab 2014; 307: E1030–E1037.
Salans LB, Horton ES, Sims EA . Experimental obesity in man: cellular character of the adipose tissue. J Clin Invest 1971; 50: 1005–1011.
Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 2015; 518: 187–196.
Yaghootkar H, Scott RA, White CC, Zhang W, Speliotes E, Munroe PB et al. Genetic evidence for a normal-weight ‘metabolically obese’ phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes 2014; 63: 4369–4377.
Yaghootkar H, Lotta LA, Tyrrell J, Smit RA, Jones SE, Donnelly L et al. Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension and heart disease. Diabetes 2016; 65: 2448–2460.
Levine JA, Lanningham-Foster LM, McCrady SK, Krizan AC, Olson LR, Kane PH et al. Interindividual variation in posture allocation: possible role in human obesity. Science 2005; 307: 584–586.
Diaz EO, Prentice AM, Goldberg GR, Murgatroyd PR, Coward WA . Metabolic response to experimental overfeeding in lean and overweight healthy volunteers. Am J Clin Nutr 1992; 56: 641–655.
Harris AM, Jensen MD, Levine JA . Weekly changes in basal metabolic rate with eight weeks of overfeeding. Obesity (Silver Spring) 2006; 14: 690–695.
Hall KD, Sacks G, Chandramohan D, Chow CC, Wang YC, Gortmaker SL et al. Quantification of the effect of energy imbalance on bodyweight. Lancet 2011; 378: 826–837.
Bray GA, Smith SR, de Jonge L, Xie H, Rood J, Martin CK et al. Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: a randomized controlled trial. JAMA 2012; 307: 47–55.
Hall K . Modeling metabolic adaptations and energy regulation in humans. Annu Rev Nutr 2012; 32: 35–54.
Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL, Jensen MD . Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc Natl Acad Sci USA 2010; 107: 18226–18231.
Pinnick KE, Nicholson G, Manolopoulos KN, McQuaid SE, Valet P, Frayn KN et al. Distinct developmental profile of lower-body adipose tissue defines resistance against obesity-associated metabolic complications. Diabetes 2014; 63: 3785–3797.
Sahakyan KR, Somers VK, Rodriguez-Escudero JP, Hodge DO, Carter RE, Sochor O et al. Normal-weight central obesity: implications for total and cardiovascular mortality. Ann Intern Med 2015; 163: 827–835.
Karpe F, Pinnick KE . Biology of upper-body and lower-body adipose tissue-link to whole-body phenotypes. Nat Rev Endocrinol 2014; 11: 90–100.
Rutkowski JM, Stern JH, Scherer PE . The cell biology of fat expansion. J Cell Biol 2015; 208: 501–512.
Gray SL, Vidal-Puig AJ . Adipose tissue expandability in the maintenance of metabolic homeostasis. Nutr Rev 2007; 65: S7–S12.
Taylor R, Holman RR . Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci (Lond) 2015; 128: 405–410.
Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008; 168: 1609–1616.
Dobson R, Burgess MI, Sprung VS, Irwin A, Hamer M, Jones J et al. Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity. Int J Obes (Lond) 2016; 40: 153–161.
Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007; 117: 2621–2637.
Garg A . Acquired and inherited lipodystrophies. N Engl J Med 2004; 350: 1220–1234.
Spiegelman BM . PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507–514.
Alligier M, Meugnier E, Debard C, Lambert-Porcheron S, Chanseaume E, Sothier M et al. Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans. J Clin Endocrinol Metab 2012; 97: E183–E192.
Kos K, Wong S, Tan B, Gummesson A, Jernas M, Franck N et al. Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose. Diabetes 2009; 58: 1780–1788.
Tam CS, Covington JD, Bajpeyi S, Tchoukalova Y, Burk D, Johannsen DL et al. Weight gain reveals dramatic increases in skeletal muscle extracellular matrix remodeling. J Clin Endocrinol Metab 2014; 99: 1749–1757.
Lumeng CN, Bodzin JL, Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 175–184.
Alligier M, Gabert L, Meugnier E, Lambert-Porcheron S, Chanseaume E, Pilleul F et al. Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men. J Clin Endocrinol Metab 2013; 98: 802–810.
Johannsen DL, Tchoukalova Y, Tam CS, Covington JD, Xie W, Schwarz JM et al. Effect of eight weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the ‘adipose tissue expandability’ hypothesis. Diabetes Care 2014; 37: 2789–2797.
Fabbrini E, Yoshino J, Yoshino M, Magkos F, Tiemann Luecking C, Samovski D et al. Metabolically normal obese people are protected from adverse effects following weight gain. J Clin Invest 2015; 125: 787–795.
McLaughlin T, Craig C, Liu L-F, Perelman D, Allister C, Spielman D et al. Adipose cell size and regional fat deposition as predictors of metabolic response to overfeeding in insulin-resistant and insulin-sensitive humans. Diabetes 2016; 65: 1245–1254.
Votruba SB, Jensen MD . Insulin sensitivity and regional fat gain in response to overfeeding. Obesity (Silver Spring) 2011; 19: 269–275.
Bouchard C, Tremblay A, Després J-P, Nadeau A, Lupien PJ, Thériault G et al. The response to long-term overfeeding in identical twins. N Engl J Med 1990; 322: 1477–1482.
Samocha-Bonet D, Campbell LV, Viardot A, Freund J, Tam CS, Greenfield JR et al. A family history of type 2 diabetes increases risk factors associated with overfeeding. Diabetologia 2010; 53: 1700–1708.
Kanaley JA, Sames C, Swisher L, Swick AG, Ploutz-Snyder LL, Steppan CM et al. Abdominal fat distribution in pre- and postmenopausal women: the impact of physical activity, age, and menopausal status. Metabolism 2001; 50: 976–982.
Sniderman AD, Bhopal R, Prabhakaran D, Sarrafzadegan N, Tchernof A . Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Int J Epidemiol 2007; 36: 220–225.
Chandalia M, Lin P, Seenivasan T, Livingston EH, Snell PG, Grundy SM et al. Insulin resistance and body fat distribution in South Asian men compared to Caucasian men. PLoS One 2007; 2: e812.
Lear SA, Humphries KH, Kohli S, Chockalingam A, Frohlich JJ, Birmingham CL . Visceral adipose tissue accumulation differs according to ethnic background: results of the Multicultural Community Health Assessment Trial (M-CHAT). Am J Clin Nutr 2007; 86: 353–359.
Lear SA, Kohli S, Bondy GP, Tchernof A, Sniderman AD . Ethnic variation in fat and lean body mass and the association with insulin resistance. J Clin Endocrinol Metab 2009; 94: 4696–4702.
Ntuk UE, Gill JM, Mackay DF, Sattar N, Pell JP . Ethnic-specific obesity cutoffs for diabetes risk: cross-sectional study of 490,288 UK biobank participants. Diabetes Care 2014; 37: 2500–2507.
Tillin T, Sattar N, Godsland IF, Hughes AD, Chaturvedi N, Forouhi NG . Ethnicity-specific obesity cut-points in the development of Type 2 diabetes - a prospective study including three ethnic groups in the United Kingdom. Diabet Med 2015; 32: 226–234.
Wulan SN, Westerterp KR, Plasqui G . Metabolic profile before and after short-term overfeeding with a high-fat diet: a comparison between South Asian and White men. Br J Nutr 2014; 111: 1853–1861.
Wulan SN, Schrauwen-Hinderling VB, Westerterp KR, Plasqui G . Liver fat accumulation in response to overfeeding with a high-fat diet: a comparison between South Asian and Caucasian men. Nutr Metab 2015; 12: 1–9.
Gillberg L, Perfilyev A, Brons C, Thomasen M, Grunnet LG, Volkov P et al. Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding. Diabetologia 2016; 59: 799–812.
Galgani J, Ravussin E . Energy metabolism, fuel selection and body weight regulation. Int J Obes (Lond) 2008; 32 (Suppl 7): S109–S119.
Lammert O, Grunnet N, Faber P, Bjornsbo KS, Dich J, Larsen LO et al. Effects of isoenergetic overfeeding of either carbohydrate or fat in young men. Br J Nutr 2000; 84: 233–245.
Sobrecases H, Le KA, Bortolotti M, Schneiter P, Ith M, Kreis R et al. Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men. Diabetes Metab 2010; 36: 244–246.
Lecoultre V, Egli L, Carrel G, Theytaz F, Kreis R, Schneiter P et al. Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans. Obesity (Silver Spring) 2013; 21: 782–785.
Bray GA, Redman LM, de Jonge L, Rood J, Smith SR . Effect of three levels of dietary protein on metabolic phenotype of healthy individuals with 8 weeks of overfeeding. J Clin Endocrinol Metab 2016; 101: 2836–2843.
Rosqvist F, Iggman D, Kullberg J, Cedernaes J, Johansson HE, Larsson A et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes 2014; 63: 2356–2368.
Chiu S, Sievenpiper JL, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ et al. Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 2014; 68: 416–423.
Ma J, Karlsen MC, Chung M, Jacques PF, Saltzman E, Smith CE et al. Potential link between excess added sugar intake and ectopic fat: a systematic review of randomized controlled trials. Nutr Rev 2016; 74: 18–32.
Chiavaroli L, de Souza RJ, Ha V, Cozma AI, Mirrahimi A, Wang DD et al. Effect of Fructose on Established Lipid Targets: A Systematic Review and Meta-Analysis of Controlled Feeding Trials. J Am Heart Assoc 2015; 4: e001700.
Koopman KE, Caan MW, Nederveen AJ, Pels A, Ackermans MT, Fliers E et al. Hypercaloric diets with increased meal frequency, but not meal size, increase intrahepatic triglycerides: a randomized controlled trial. Hepatology 2014; 60: 545–553.
Seyssel K, Alligier M, Meugnier E, Chanseaume E, Loizon E, Canto C et al. Regulation of energy metabolism and mitochondrial function in skeletal muscle during lipid overfeeding in healthy men. J Clin Endocrinol Metab 2014; 99: 1254–1262.
Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CWJ . Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 2008; 341: 1097–1105.
Hamer M, Stamatakis E . Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab 2012; 97: 2482–2488.
Cornier MA, Von Kaenel SS, Bessesen DH, Tregellas JR . Effects of overfeeding on the neuronal response to visual food cues. Am J Clin Nutr 2007; 86: 965–971.
Cornier MA, Salzberg AK, Endly DC, Bessesen DH, Rojas DC, Tregellas JR . The effects of overfeeding on the neuronal response to visual food cues in thin and reduced-obese individuals. PLoS One 2009; 4: e6310.
Cornier MA, Grunwald GK, Johnson SL, Bessesen DH . Effects of short-term overfeeding on hunger, satiety, and energy intake in thin and reduced-obese individuals. Appetite 2004; 43: 253–259.
Knudsen SH, Hansen LS, Pedersen M, Dejgaard T, Hansen J, Hall GV et al. Changes in insulin sensitivity precede changes in body composition during 14 days of step reduction combined with overfeeding in healthy young men. J Appl Physiol 2012; 113: 7–15.
Walhin JP, Richardson JD, Betts JA, Thompson D . Exercise counteracts the effects of short-term overfeeding and reduced physical activity independent of energy imbalance in healthy young men. J Physiol 2013; 591 (Pt 24): 6231–6243.
van der Meer RW, Hammer S, Lamb HJ, Frolich M, Diamant M, Rijzewijk LJ et al. Effects of short-term high-fat, high-energy diet on hepatic and myocardial triglyceride content in healthy men. J Clin Endocrinol Metab 2008; 93: 2702–2708.
Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Slander K et al. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr 2012; 96: 727–734.
Boon MR, Bakker LE, Haks MC, Quinten E, Schaart G, Van Beek L et al. Short-term high-fat diet increases macrophage markers in skeletal muscle accompanied by impaired insulin signalling in healthy male subjects. Clin Sci 2015; 128: 143–151.
Jebb SA, Siervo M, Fruhbeck G, Goldberg GR, Murgatroyd PR, Prentice AM . Variability of appetite control mechanisms in response to 9 weeks of progressive overfeeding in humans. Int J Obes (London) 2006; 30: 1160–1162.
Cahill F, Shea JL, Randell E, Vasdev S, Sun G . Serum peptide YY in response to short-term overfeeding in young men. Am J Clin Nutr 2011; 93: 741–747.
Wadden D, Cahill F, Amini P, Randell E, Vasdev S, Yi Y et al. Serum acylated ghrelin concentrations in response to short-term overfeeding in normal weight, overweight, and obese men. PLoS One 2012; 7: e45748.
Wadden D, Cahill F, Amini P, Randell E, Vasdev S, Yi Y et al. Circulating glucagon-like peptide-1 increases in response to short-term overfeeding in men. Nutr metab (Lond) 2013; 10: 33.
Germain N, Galusca B, Caron-Dorval D, Martin JF, Pujos-Guillot, Boirie Y et al. Specific appetite, energetic and metabolomics responses to fat overfeeding in resistant-to-bodyweight-gain constitutional thinness. Nutr Diabetes 2014; 4: e126.
The authors declare no conflict of interest.
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Cuthbertson, D., Steele, T., Wilding, J. et al. What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?. Int J Obes 41, 853–865 (2017). https://doi.org/10.1038/ijo.2017.4